There are limited treatment options for patients at high risk of ventricular arrhythmic events. Beta- blockers alone do not provide enough protection, sotalol has limited effectiveness, and amiodarone although effective in some groups of patients is used infrequently due to its side effects and limitations of a long-term use. Ischemia and cardiomyopathies are associated with a sodium overload of myocardial cells. Late sodium current plays a pivotal role in this process. Sodium overload leads to calcium overload of myocardial cells with consequent increased vulnerability of myocardium to ventricular tachyarrhythmias as well as increased impairment of diastolic relaxation of myocardium thereby augmenting the risk of ischemia and myocardial damage. Ranolazine is a novel drug with anti-ischemic and anti-arrhythmic properties that uniquely blocks late sodium current, decreases intracellular calcium overload, and improves diastolic relaxation of the ventricles. The anti-ischemic and anti-arrhythmic properties of ranolazine might decrease the likelihood of arrhythmic events and improve the clinical course of patients at the risk for ventricular arrhythmias. We propose a randomized double-blind placebo-controlled clinical trial enrolling 1,200 high-risk ICD patients who will be treated with ranolazine or placebo in addition to optimal medical therapy. Primary aim of the study is to determine whether ranolazine administration in high-risk patients with ICDs contributes to a decrease in the number of patients reaching a composite arrhythmia endpoint consisting of ventricular tachycardia or fibrillation requiring appropriate ICD shocks, or death (whichever occurs first). Secondary aims of the study are: 1) to determine whether ranolazine administration will decrease the likelihood of composite primary endpoints consisting of hospitalization for cardiac causes or death, 2) to determine whether ranolazine administration will decrease the likelihood of a composite secondary endpoint consisting of CHF hospitalization or death, 3) to determine whether ranolazine therapy will decrease the number of repeated hospitalizations for cardiac causes, 4) to assess whether ranolazine administration will decrease the likelihood of repeated ICD therapies, 5) to evaluate whether ranolazine administration will decrease the likelihood of appropriate ICD shocks, 6) to determine whether ranolazine therapy will be associated with improvement in exercise capacity measured by the 6-minute walk test (6MWT) and in the quality of life measured by the Minnesota Leaving with Heart Failure Questionnaire (MLHFQ), and 7) to evaluate the safety of ranolazine therapy utilizing ICD interrogation data documenting all types of ventricular tachyarrhythmias (including torsade de pointes). This proposal consists of two clustered applications covering respective components of the trial: Clinical Core - Leading Application, and Data Coordination Center. (End of Abstract) PUBLIC HEALTH RELEVANCE: The trial with late sodium channel blockade ranolazine in high-risk ICD patients is very much needed since there is no safe and effective treatment for a large number of patients with high risk of ventricular tachyarrhythmias. It is of interest to clinicians, NHLBI, and patients to improve the very low survival of patients at increased risk of ventricular tachyarrhythmias. It is worth stressing that late sodium current blockade represents a new scientifically attractive concept of anti-arrhythmic therapy after two decades of no significant developments in pharmacologic treatment of ventricular arrhythmias. Conducting such a trial might open the door to the development of an entire line of compounds targeting the late sodium current as their main mode of anti-arrhythmic action.